Topical drug delivery using phosphatidylcholine

ABSTRACT

The present invention relates to compositions and methods for transdermal drug delivery comprising formulating a phosphatidylcholine carrier composition containing the drug and applying the composition to the skin.

PRIOR APPLICATION

This application is a divisional patent application of copending U.S.patent application Ser. No. 10/448,632 for “Topical Drug Delivery UsingPhosphatidylcholine,” filed May 30, 2003, which claims priority benefitsunder 35 U.S.C. §119(e) of U.S. Provisional Patent Application Ser. No.60/384,597 filed May 31, 2002.

FIELD OF THE INVENTION

The present invention relates to a topical drug delivery composition andmethod. More specifically, this invention relates to topical drugdelivery compositions and methods using phosphatidylcholine.

BACKGROUND OF THE INVENTION

Transdermal drug delivery systems may be designed to act locally at thepoint of application or to act systemically by entering the body's bloodcirculation. In these systems, delivery may be achieved by directtopical application of a substance or drug in the form of an ointment orthe like, or by adhesion of a patch with a reservoir that holds the drugand releases it to the skin in a time-controlled fashion.

Transdermal delivery systems for agents such as drugs, pain relievingcompounds, vitamins, and skin improving compounds have been in use for anumber of years. However, these systems have typically only been usefulfor transdermal delivery of relatively small molecules. The skin'sporous structure permits such small molecules to pass from the epidermisto the dermis via diffusion. These transdermal delivery systems such ascreams have been developed for use with analgesics and skin refiningcompounds. Transdermal systems using a patch have been developed fornicotine and estrogen therapies. Estradiol technologies are described inU.S. Pat. No. 6,521,250 to Meconi, et al. However, large molecules, suchas insulin, are not able to diffuse through the skin. To date there hasnot been an effective and economical method to transport such moleculesthrough the epidermis to enter the bloodstream via the dermalvasculature.

It has been proposed that molecules, potentially including largermolecules, can be transported through the skin when such molecules arecontained within spherical vesicles, variously called microparticles,microspheres, liposomes, lipid vesicles, transfersomes, formed byhydrating a phospholipid. The resulting vessels are water-insoluble andare dispersed and suspended in a liquid base material which is appliedto the skin to deliver the drug. U.S. Pat. No. 6,165,500 to Cevcdiscloses “transfersomes,” which are vesicles containing both a lipidand surfactant, to achieve transdermal delivery, based on a theory thatosmotic pressure will drive the transfersomes through the dermis. Othersolutions have been proposed, including the use of ultrasound devices togenerating shock waves to enlarge pores, use of electric current todrive substances across skin, and the use of microneedles to pierce skinand deliver drugs into bloodstream. (See More Than the Patch: New Waysto Take Medicine Via Skin, New York Times, Jul. 2, 2002, page F5.

There remains a need for a transdermal drug delivery system with theimproved skin permeability and ability to transport a wider range ofsubstances or drugs. This problem is particularly apparent in thetransdermal delivery of substances composed of large molecules, such aspolypeptides or proteins, which do not readily pass through the pores ofthe skin. Absent such a transdermal drug delivery system, the use ofinjections to deliver these substances will remain the conventionaldosage method, despite the pain, complicated administration and generalinvasiveness involved therein.

SUMMARY OF THE INVENTION

The present invention relates to compositions and methods of transdermaldrug delivery comprising formulating a composition containing the drugin a crystallized phosphatidylcholine carrier and applying thecomposition to the skin.

DETAILED DESCRIPTION OF THE INVENTION

Phosphatidylcholine is used as a carrier for the topical drug deliveryof macromolecules in the practice of this invention. Phosphatidylcholineis a basic component of cell membrane bilayers and the main phospholipidcirculating in the plasma. Phosphatidylcholine is highly absorbable andsupplies choline which is needed to facilitate movement of fats and oilsacross and maintain cell membranes in animals.

Phosphatidylcholine compositions (herein abbreviated “PC compositions”)of the present invention are formulated to contain macromoleculessoluble in PC, which are then applied to skin for transdermal deliveryof the macromolecule. PC compositions of the invention are efficaciousin the delivery of macromolecular drugs that are conventionallyadministered intramuscularly, intravenously or orally, including, butnot limited to polypeptides such as insulin and somatropin,prostaglandins, glucocorticoids, estrogens, androgens, and the like.

It is an advantage of the invention that topical delivery is easier andpleasanter as an administration route than injections, particularly fordrugs such as insulin that must be given to patients over a period oftime, or for a lifetime. Furthermore, unlike oral administration where asubstantial amount of the drug can be destroyed in the digestiveprocess, the drugs in a topical application are not wasted. Topicalapplication allows a steady diffusion of the drug to the desired targetarea without the cyclic dosages typical of orally or parenterallyadministered drugs.

Typical phosphatidylcholine compositions of the present invention arenonpolar and contain about 85% phosphatidylcholine. By“phosphatidylcholine” is meant a mixture of stearic, palmitic, and oleicacid diglycerides linked to the choline ester of phosphoric acid,commonly called lecithin. Many commercial lecithin products areavailable, such as, for example, Lecithol®, Vitellin®, Kelecin®, andGranulestin® because lecithin is widely used in the food industry.Compositions of the invention can contain synthetic or natural lecithin,or mixtures thereof. Natural preparations are preferred because theyexhibit desirable physical characteristics and are both economical andnontoxic.

The macromolecular drugs are mixed with the PC composition underconditions to become entrapped in a phosphatidylcholine bilayer.Phosphatidylcholine forms a bilayer entrapping the macromolecular drug,which may be a polypeptide, contributing to the stability of the activemolecule and enhancing penetration. The PC composition therein comprisesa carrier-drug combination to be applied topically.

While not wishing to be bound by any particular theory, it is believedthat the following mechanism illustrates how the PC composition acts toefficiently transport the drug across the epidermis, maximizingpenetration of the drug. The PC composition, in liquid crystal phase, isloosely arranged in multilamellar fashion, with the drug being bondedand entrapped within the lipid bilayers formed by the PC composition.This forms a loosely arranged, yet stable, PC composition carrier-drugcomplex. When placed on the epidermis, the carrier-drug complex beginsto diffuse through the epidermis. The phosphatidylcholine molecularchain remains loosely linked with the drug molecular chain and thediffusing phosphatidylcholine molecules “drag” the drug molecules alongas they pass through the skin layers. Moreover, the phosphatidylcholinemolecules may begin to separate from the loosely arranged carrier-drugcomplex and become integrated into the dermis. As thephosphatidylcholine molecules separate from the crystallizedphophoslipid bilayer structure of the carrier-drug complex the drugmolecules are released. As these drug molecules are released, they arenow within into the dermis and may enter the dermal vasculature so theymay act accordingly in the bloodstream. Drug molecules which were oncetoo large to diffuse, by themselves, into the pores of the epidermis,have instead been forced through the epidermis by phosphatidylcholinecarriers which naturally enter and integrate into lipid bilayerstructures within the cells of the epidermis and/or dermis andresultantly are required to release their bonds to the drug moleculesand set them free within the dermis.

Preferred PC compositions comprise phosphatidylcholine in crystal phaseto increase fluidity of the lipid bilayer formed. By reducing rigidityand loosening the phospholipid bilayer of the PC composition, largermolecules may embed therein and penetration of the carrier-drugcomposition by the cell membrane is facilitated. The skin is morepermeable to the fluid, less structured lipid bilayer of thePC/carrier-drug composition applied thereon than to the drug by itself,or entrapped in an organized, arranged vesicle such as a liposome. Theloosely packed lipid bilayer of the crystallized carrier-drugcomposition integrates into the cell membrane, and as a result, hastransported the drug so it can enter the bloodstream to act upon thebody. The PC composition may be a multilamellar liquid crystal phase ora liquid crystal phase suspension in water which may be converted tomultilamellar liquid lipid vesicles.

In preferred embodiments, nonpolar preparations of phosphatidylcholineare formulated to contain adjunct ingredients, e.g., lipoic acid andascorbyl palmitate, in addition to the macromolecular drug. The adjunctingredients act synergistically to help to minimize degradation and thuspreserve the integrity of the insulin polypeptide chains, and to enhancetransdermal penetration of active insulin so that it can be absorbed bythe dermal vasculature.

Preferred PC compositions of the invention contain somepolyenylphosphatidylcholine (herein abbreviated “PPC”) to enhanceepidermal penetration. By “polyenylphosphatidylcholine” is meant anyphosphatidylcholine bearing two fatty acid substituents, wherein atleast one is an unsaturated fatty acid with at least two double bondssuch as linoleic acid. Preferred PPCs contain a mixture of substitutentssuch as those found in natural products such as soybean lecithin, whichcontains 11.7% palmitic, 4.0% stearic, 8.6% palmitoleic, 9.8% oleic,55.0% linoleic, and 4.0% linolenic acid substituents and is a by-productof soybean oil manufacture.

Certain types of soybean lecithin, for example, contain higher levels ofpolyenylphosphatidylcholine, with dilinoleoylphosphatidylcholine(18:2-18:2 phosphatidylcholine) as the most abundant phosphatidylcholinespecies, than conventional food grade lecithin, and are useful informulating phosphatidylcholine insulin compositions of the invention.Alternatively, conventional soybean lecithin is enriched with PPC byadding soybean extracts containing high levels of PPC. As used herein,this type of phosphatidylcholine is called “PPC-enriched”phosphatidylcholine, even where the term encompasses lecithin obtainedfrom natural sources exhibiting PPC levels higher than ordinary soybeanvarieties. These products are commercially available from AmericanLecithin, Rhône-Poulenc and other lecithin vendors. American Lecithinmarkets its products with a “U” designation, indicating high levels ofunsaturation; Rhône-Poulenc's product is a soybean extract containingabout 42% dilinoleoylphosphatidylcholine and about 24%palmitoyllinoleylphosphatidylcholine (16:0-18:2 PC) as the major PCcomponents.

PC compositions are used for transdermal polypeptide delivery in somepreferred embodiments. Polypeptide drugs that are deliveredtransdermally using formulations can be small, e.g., ocytocin andvasopressin nonapeptides or large, e.g., insulin, gonadotropin, andsomatropin. PC compositions of the invention deliver drugs including,but are not limited to, oxytocin, vasopressin, insulin, somatotropin,calcitonin, chorionic gonadotropin, menotropins, follitropins,somatostatins, progestins, and combinations of any of these. These drugsare readily available from a variety of commercial sources. Insulin, forexample, is marketed under the tradenames Humulin®, Novolin®, Humalog®,and Inutral®. Somatotropin is marketed under the tradenames Gentropin®,Humatrope®, Nutropin®, and Serostim®. Some of these products and otherpolypeptides contain porcine sequences. Preferable compositions of theinvention are preferably formulated with recombinant human polypeptides.It is an advantage of the invention that PC insulin compositions areformulated with commercially available ingredients.

One, non-limiting, example of an insulin topical preparation wasformulated by combining 0.75% methyl paraben with a commercialphosphatidylcholine preparation marketed as a solution denoted NAT-8729(containing PEG-400 at 40% and P.G. at 5%) by mixing for an hour or moreto emulsify. To this is slowly added Dow Corning Fluid 200-5 or 10 cst(1% by weight), the formulation is mixed, and then Dow Corning Fluid 190(1% by weight) is slowly added, and the formulation is further mixed toprovide a stock insulin carrier. Prior to topical administration,insulin is added at a level of about 3.8 mg/ml to provide about 100insulin units per ml.

Another, non-limiting, example of a pituitary growth hormone(somatotropin) composition was formulated with 85% phosphatidylcholineto which lipoic acid and ascorbyl palmitate was added as antioxidants.Somatotropin readily dispersed in phosphatidylcholine and remainedstable in it. Growth hormone appeared to penetrate the skin well whenthe composition was topically applied.

It is appreciated that the foregoing is illustrative and not limiting ofthe invention, and that various changes and modifications to thepreferred embodiments described above will be apparent to those skilledin the art. Such changes and modifications can be made without departingfrom the spirit and scope of the present invention, and it is thereforeintended that such changes and modification be covered by the followingclaims.

1. A composition comprising crystallized phosphatidylcholine andpolypeptide drug molecules entrapped within the phosphatidylcholine fortransdermal delivery of the polypeptide drug molecules into dermalvasculature.
 2. The composition of claim 1, wherein the polypeptide drugmolecules are selected from the group consisting of oxytocin,vasopressin, insulin, somatotropin, calcitonin, chorionic gonadotropin,menotropins, follitropins, somatostatins, progestins, and combinationsof any of these.
 3. The composition of claim 1, wherein thephosphatidylcholine is enriched with polyenylphosphatidylcholine.
 4. Thecomposition of claim 3, wherein the phosphatidylcholine is purepolyenylphosphatidylcholine.
 5. The composition of claim 1, wherein thecomposition contains about 85% phosphatidylcholine.
 6. The compositionof claim 1, wherein the phosphatidylcholine is soybean lecithin.
 7. Thecomposition of claims 1, further comprising one or more adjunctingredients to preserve integrity of the polypeptide drug molecules,selected from the group consisting of ascorbyl palmitate, lipoic acid,and combinations of these.
 8. The composition of claim 2, wherein thephosphatidylcholine is enriched with polyenylphosphatidylcholine.
 9. Thecomposition of claim 8, wherein the phosphatidylcholine is purepolyenylphosphatidylcholine.
 10. The composition of claim 2, wherein thecomposition contains about 85% phosphatidylcholine.
 11. The compositionof claim 2, wherein the phosphatidylcholine is soybean lecithin.
 12. Thecomposition of claims 2, further comprising one or more adjunctingredients to preserve integrity of the polypeptide drug molecules,selected from the group consisting of ascorbyl palmitate, lipoic acid,and combinations of these.
 13. A topical composition for transdermaldelivery of macromolecular drugs, comprising: a carrier containingcrystallized phosphatidylcholine enriched withpolyenylphosphatidylcholine; and at least one macromolecular drugentrapped within the crystallized phosphatidylcholine carrier fortransdermal delivery into dermal vasculature.
 14. The composition ofclaim 13, wherein the polypeptide drug molecules are selected from thegroup consisting of oxytocin, vasopressin, insulin, somatotropin,calcitonin, chorionic gonadotropin, menotropins, follitropins,somatostatins, progestins, and combinations of any of these.
 15. Thecomposition of claim 13, further comprising at least one adjunctingredient selected from the group consisting of ascorbyl palmitate,lipoic acid, and combinations of these, to preserve integrity of themacromolecular drug during delivery.
 16. The composition of claim 13,wherein the phosphatidylcholine carrier is purepolyenylphosphatidylcholine.
 17. The composition of claim 13, whereinthe composition contains about 85% phosphatidylcholine.
 18. Thecomposition of claim 13, wherein the phosphatidylcholine carrier issoybean lecithin.